Benzodipyrones

ABSTRACT

Certain benzodipyrones, e.g., 4,10-dioxo-2,8-dicarboxy-5methoxy-4H,10H-benzo(1,2-b:3,4-b&#39;&#39;) dipyran disodium salt and many others which are disclosed, inhibit the release and/or action of toxic products which arise from the combination of certain types of antibody and specific antigen; and are useful in the treatment of conditions - such as asthma, hay fever, etc. - in which antigen reactions are responsible for said conditions.

United States Patent [1 1 Cairns et al.

[ 1 Feb.27,1973

BENZODIPYRONES Inventors: Hugh Cairns, Sandbach, Cheshire; Robert Minshull, Brereton, Cheshire, both of England Assignee: Fisons Limited,Suffolk, England Filed: Aug. 7, 1970 Appl. N0.: 62,170

Related US. Application Data Continuation-impart of Ser. No. 751,753,Aug. 12, 1970, abandoned.

US. Cl. ..260/345.2, 260/345.5, 260/295 F,

260/326.3, 424/283 Int. Cl. ..C07d 7/34 Field of Search ..260/345.2,345.5, 29 5 F, 326.3

[56] References Cited UNITED STATES PATENTS 3,427,324 2/1969 Fitzmaurice ..260/ 345.2 3,484,445 l2/ 1969 Lee et al ..260/345.2

Primary ExaminerJohn M. Ford Attorney-Wenderoth, Lind & Ponack [5 7]ABSTRACT 28 Claims, No Drawings BENZODIPYRONES This is acontinuation-in-part application of Applicants copending application,Ser. No. 751,753, filed Aug. 12, 1970, now abandoned.

The present invention relates to novel compounds, their preparation anduse.

According to the invention there are provided, as new compounds,benzodipyrones of the Formula I,

P I I Q II I R 00111 0 in which one or more adjacent pairs of P, Q, Rand T, together form the chain -CO-CR,#Z(CCOH)O- which may be bonded tothe benzene ring in either sense; the remainder of P, Q, R and T are thesame or different and each is hydrogen; alkyl containing from one tocarbon atoms (e.g., methyl, ethyl, butyl, pentyl, and hexyl groups);alkyl containing from one to 10 carbon atoms and carrying a halo;hydroxy; lower alkoxy, e.g., methoxy, ethoxy, propoxy or pentoxy;acetoxy; carboxy; amino; lower alkylamino e.g., ethylamino, butylaminoor pentylamino; lower di-alkylamino, e.g., dimethylamino, diethylamino,dibutylamino, dipentylamino; or a hydroxylamino substituent group;unsaturated alkyl containing from one to 10 carbon atoms (e.g., alkenylsuch as allyl and propargyl); phenylalkyl (e.g., benzyl and phenethylgroups), halophenylalkyl or alkylphenylalkyl wherein the alkyl groupscontain from one to 10 carbon atoms; phenyl; naphthyl; or phenyl andnaphthyl carrying a halo, lower alkyl, nitro, carboxy or hydroxysubstituent group; pyridyl; furyl; pyrrolyl; cycloalkyl containing fromfour to six carbon atoms (e.g., cyclopentyl or cyclohexyl); cycloalkylcontaining from four to six carbon atoms and carrying a hydroxyl, loweralkoxy or carboxy substituent group nitrile; nitro; nitroso; hydroxy;alkoxy containing one to 10 carbon atoms e.g., methoxy, ethoxy orpropoxy alkoxy containing from one to l carbon atoms and carrying ahydroxy, lower alkoxy, carboxy halo, amino, lower alkylamino, or lowerdialkylamino substituent group; alkenyloxy or alkynyloxy containing fromone to 10 carbon atoms; benzyloxy; phenyloxy; naphthyloxy; pyridyloxy;cyclohexyloxy; cyclopentyloxy; epoxyloweralkoxy; amino; lower alkylaminoe.g., ethylamino and propylamino lower dialkylamino e.g. dimethylaminoand diethylamino cycloalkylamino containing from 4 to 6 carbon atoms;phenylamino; naphthylamino; diphenylamino; haloloweralkylamino; loweralkenylamino; aminoloweralkylamino, hydroxylamino; lower acyl amino;ureyl; thioureyl; guanidino; thiol; lower alkyl thiol; phenyl thiol;sulphonic acid; halogen e.g., chlorine, bromine, or iodine or one ormore of P, Q, R and T may be a group OY wherein Y is an alkyl grouphaving from one to 10 carbon atoms substituted by lower alkyl orphenyllower alkyl in which one or more of the CH groups has beenreplaced by oxygen, sulphur or carbonyl, which alkyl or phenyl-loweralkyl may carry one or more hydroxyl or carboxyl substituent groups; oran adjacent pair of P, Q, R and T (together with the adjacent carbonatoms in the benzene ring) together form a benzene ring, or a (wherein Ris hydrogen or lower alkyl or lower alkoxy and R is hydrogen, or R and Rtogether form a =0 group), and each R may be the same or different andis hydrogen, alkyl containing from one-l0 carbon atoms, alkoxycontaining from one-l0 carbon atoms or phenyl and pharmaceuticallyacceptable derivatives thereof. It will be appreciated that the chainCO-CR =C(COOH)-0 may be bonded to the benzene ring in either sense toform the rings and reference to one chain or ring is intended herein andinv the claims to denote bonding in both senses.

Preferred compounds of the invention include those wherein those of P,Q, R and T not forming a CO-- CR =C(COOH)O chain are hydrogen orhalogen, hydroxy, nitro, lower alkyl, lower alkenyl, benzyl, phenyl,lower alkoxy, lower alkenyloxy, phenyl, benzyloxy or the fused ringsubstituents specified above; and such groups carrying a halogen,hydroxy or lower alkoxy substituent. Particularly preferred compoundsare those carrying hydrogen or a halogen (especially chlorine orbromine), nitro or lower alkyl or alkoxy group containing from one tosix carbon atoms which may carry a hydroxy, lower alkoxy or phenylsubstituent.

Also preferred are compounds of the formula:

wherein an adjacent pair of P, Q, R and 'I together forms the chainCOCH#I(COOH)O may be bonded to the benzene ring in either sense; and theother two P, Q, R and T may be the same or different and each ishydrogen, halogen, nitro, lower alkyl, lower alkoxy, or a lower alkyl oralkoxy group carrying a hydroxy, lower alkoxy or phenyl substituent.

As a further feature of our invention we provide compounds of Formula Iin which those of P, Q, R and T which do not form a chain COCR,=C(COOH)selected from the group consisting of hydrogen, hydroxy, nitro, halogen,lower alkyl, lower alkoxy or lower alkenyloxy groups (which groups maycarry a hydroxy or lower alkoxy substituent), a benzyl group or anadjacent pair of P, Q, R and T may, together with the carbon atoms onthe benzene ring form a fused oxygen containing 5 membered ring, and

each R, is selected from the group consisting of hydrogen, alkylcontaining from one to carbon atoms, alkoxy containing from one to 10carbon atoms and phenyl.

As a yet further feature of our invention we provide compounds offormula I in which R, is hydrogen and those of P, Q, R and T which donot form a COCR,= C(COOH)-O chain are selected from methoxy, hydroxy,nitro, methyl, bromo, benzyloxy, ethyl, chloro, allyloxy, butyl, propyland pentyl.

It will be appreciated that certain of the above values of the P, Q, R,T, P, Q, R and T include groups which might be detrimentally affected bythe reactants and/or reaction conditions used to introduce other groupsor the desired rings into the molecule. In such cases the affected groupor site may be blocked or shielded, for example by alkylation,acetylation or by the blocking of the reactive site with a removablegroup such as a cyano or nitro group.

' Each R, may be the same or different and have the values specifiedabove, particularly hydrogen, lower alkyl, e.g., methyl, ethyl, propyl,or pentyl; lower alkoxy corresponding to such alkyl groups; or a phenylgroup. It is usually preferred that each R, group be the same, andfurther, that each is hydrogen.

Pharmaceutically acceptable derivatives of the compound according to theinvention include pharmaceutically acceptable salts, notablywater-soluble salts, esters and amides of one or more of the carboxylicacid functions present and esters of any hydroxylic functions present.

Salts of the compounds which may be mentioned are salts withphysiologically acceptable cations, for example, ammonium salts; metalsalts, such as alkali metal salts (e.g., sodium, potassium and lithiumsalts) and alkaline earth metal salts (e.g., magnesium and calciumsalts); and salts with organic bases, e.g., amine salts such aspiperidine, triethanolamine and diethylaminoethylamine salts.

Esters which may be mentioned include simple alkyl esters derived fromalcohols containing up to 10 carbon atoms; amides which may be mentionedinclude simple amides and more complex amides with amino acids such asglycine.

COOH

The pharmaceutically acceptable derivatives of the compounds of theinvention may be prepared by conventional techniques. Thus, salts may beprepared by the use of alkaline conditions during the recovery andpurification of the compound. Alternatively, the free acid may beobtained and subsequently converted to a desired salt by neutralizationwith an appropriate base, e.g., an organic amine, or alkali such as analkali metal (e.g., sodium or potassium) or alkaline earth metal (e.g.,calcium or magnesium) hydroxide, carbonate or bicarbonate, preferably amild base or alkali such as sodium carbonate or bicarbonate. Where thecompound is recovered in the form of a salt this salt may be convertedto a more desirable salt, for example by a metathetical process. Theesters may be obtained as a result of having used appropriate startingmaterials, for example by the reaction of a dialkyl oxalate with anacylbenzene of Formula V as hereinafter described; or may be formed bythe reaction of an appropriate alcohol, alkyl sulphate or halo-compoundwith free carboxyl groups in the compound. Alternativelytransesterification techniques may be used to exchange one ester groupfor another. The amides may be readily obtained, for example, bydehydration of the ammonium salt or by reaction of the carboxy estergroups in the compound with an appropriate amino compound such as aprimary or secondary amine or an amino acid.

The new compounds of the invention have been shown to inhibit therelease and/or action of toxic' products which arise from thecombination of certain types of antibody and specific antigen, e.g., thecombination of reaginic antibody with specific antigen. In man, it hasbeen found that both subjective and objective changes which result fromthe inhalation of specific antigen by sensitized subjects are markedlyinhibited by prior administration of the new compounds. Thus, the newcompounds are of great value in the treatment of extrinsic" allergicasthma. It has also been found that the new compounds are of value inthe treatment of so-called intrinsic asthma (in which no sensitivity toextrinsic antigen can be demonstrated). In in vitro tests, the compoundshave been shown to reduce the release of pharmacologically activesubstances from passively sensitized human lung tissue after exposure tospecific antigen using a modification of the in vitro technique orMongar and Schild (J.L. Mongar and ED. Schild, J. Physiol, Vol. 150(1960), pp. 546-564). The new compounds may also be of value in thetreatment of other conditions in which antigen reactions are responsiblefor disease, for example, hay fever, urticaria and auto-immune diseases.

According to a further feature of the invention, therefore, there isprovided a pharmaceutical composition comprising a compound of generalFormula I, or a The compositions may be formulated in the conventionalmanner with the customary ingredients. For example, the compositions maybe put up as aqueous solutions or suspensions, as powders or in tablet,cream, lotion or syrup form.

The compounds of the invention find especial use when inhaled by theuser, notably in the treatment of allergic asthma. For such use, thecompounds of the invention, preferably in the form of a salt such as thesodium salt, are dissolved or suspended in water and may be applied bymeans of a conventional nebulizer. However, the administration ofmedicaments by means of a pressurized dispensing container, i.e., anaerosol dispenser, is an alternative to nebulizer administration. Foradministration from an aerosol dispenser, the medicament is dissolved orsuspended in the liquefied propellant medium. Where the medicament isnot soluble in the propellant, it may be necessary to add asurface-active agent to the composition in order to suspend themedicament in the propellant medium, and such surface-active agents maybe any of those commonly used for this purpose, such as non-ionicsurfaceactive agents. However, we prefer to use the anionic dialkylsulphosuccinate or alkyl benzene sulphonate surface-active agents. Theuse of such surface-active agents and the advantages which stemtherefrom are more fully described in British Pat. Specification No.1,063,512.

The compositions of the invention may also be administered in the formof powders by means of an insufflator device, such as that described inour French Pat. Specification 1,471,722. In order to improve theproperties of the powder, it may be desired to modify the surfacecharacteristics of the powder particles, for example by coating themwith a pharmaceutically acceptable material such as sodium stearate. Inaddition, the fine particle sized powders may be mixed with a coarserdiluent material such as lactose.

While the inhalation of medicament has been described above withparticular reference to oral administration, it will be appreciated thatit may be desirable to administer the medicament nasally. The terminhalation is therefore used herein and in the claims to denote, wherethe context permits, both oral and nasal administration.

The composition of the invention may also be administered as tablets,syrups and the like or by intradermal or intravenous injection in theconventional manner.

In addition to the internal administration, the compounds of theinvention may find use in compositions for topical application, e.g., ascreams, lotions or pastes for use in dermatological treatments.

In addition to the compound of the invention and the ingredientsrequired to present the compound in a form suitable for the selectedmode of administration, we have found that other active ingredients maybe present in the composition of the invention. Thus, in compositionsfor administration by inhalation, we have found that it is beneficial toinclude a bronchodilator. Any bronchodilator may, within reason, beused. Suitable bronehodilators include isoprenaline, adrenaline,orciprenaline, isoetharine and derivatives thereof, particularly thesalts thereof. The use of isoprenaline sulphate is preferred. The amountof bronchodilator used will vary over a broad range, depending, interalia, upon the nature and activity of the bronchodilator and thecompound of the invention used. However, the use a minor proportion(i.e., less than 50 percent by weight) of the bronchodilator ispreferred. We have found that the use of from 0.1 to 10 percent byweight of the bronchodilator based on the weight of the compound of theinvention is satisfactory.

From a further aspect, the invention therefore provides a compositionwhich comprises a compound of the formula I or a pharmaceuticallyacceptable derivative thereof in admixture with a bronchodilator, whichlatter is preferably present in less than 50 percent, especially 0.1 to10 percent, by weight of the former.

As indicated above, the compounds of the invention may be used toinhibit the effects of antibody-antigen reactions and are of especialuse in the prophylactic treatment of allergic airway diseases. ln suchtreatments the compound or composition of the invention is administeredby the chosen method to the site of the antibody-antigen reaction in thetherapeutically effective amount. The treatment may be one whichrequires repeated dosages of the medicament at regular intervals. Theamount and frequency of medicament administered will depend upon manyfactors and no concise dosage rate or rgimen can be generally stated.However, as a guide we have found that, where the compounds areadministered by inhalation to a patient suffering from acute allergicasthma, therapeutically useful results are achieved when the compoundsare administered at a dosage rate of from 0.1 to 50 mgs. Where thecompounds are administered by the oesophagal route, larger dosages maybe given.

The invention thus also provides a method for inhibiting the effects ofan antibody-antigen reaction which comprises the prior application tothe known or expected area of the antibody-antigen reaction of atherapeutically effective amount of a compound of Formula I or of apharmaceutically acceptable derivative thereof.

The compounds of the invention may be prepared from compounds of theformula wherein A, and A, together form the chain -CO CR,=C(COOH)O-, achain convertible thereto such as a -COCR,=C(D)O or COCHR,-- CH(D)Ochain (wherein D is a COOR group or a group convertible thereto and R,is hydrogen or an alkyl group containing from one to 10 carbon atoms),are groups convertible to the desired chain or to a chain convertiblethereto, or are derivatives or precursors of such groups or chains; oneor more adjacent pairs of the groups B,, B B and B, are the groups A,and A,, the pairs of groups A, and A may have the same or differentvalues except that all pairs of groups cannot form -CO-CR,=C(COOH)O-chains; and the remainder of the groups 13,, B B and B, are hydrogen orappropriate substituents.

It will be appreciated that the compounds of the invention possess atleast two I R1 1 CODE rings and that these may be the same. Each ofthese 0 rings may be introduced in separate stages by different orsimilar methods or may be introduced together in a single reactionstage. It is also possible to introduce in separate stages precursors ofone of the desired rings, for example a chain COCH CH(COOl-l)O-, by onemethod, to introduce the same or another precursor for the other ring,e.g., a chain -C0 CH(CH )--CH(COOH)O by a different method, and then toconvert the two precursors into the desired rings in a final commonreaction stage, e.g., by dehydrogenation. For convenience thepreparation of the compounds of the invention will be described in termsof the conversion of only one of the pairs of groups A and A to thedesired ring. The other ring may be present initially, be formed duringthe formation of the first ring, or be introduced later by the same or adifferent process. Where both rings are to be introduced one afteranother it may be necessary to shield or block the sites at which thesecond ring is to be introduced. Such shielding or blocking may beachieved by conventional methods as indicated above. The general formulafor the starting material,

is therefore to be construed as covering compounds may be achieved by avariety of methods. For example the desired ring may be formed bycyclizing compounds of the general formulas:

Br COHCOCOR" wherein R" is an OH group or a group convertible theretoand M is hydrogen, an alkali-metal cation or an alkyl group;

dehydrogenation of the product if required. The desired ring may also beformed by modification of an already formed chromone or chromanone ring[i.e., compounds wherein A and A together form the chain--C0-CR,=C(D)--O or COCHR --CH(D)- O-], for example by oxidation ofsubstituents in the 2- position of the ring, by dehydrogenation or byintra molecular rearrangement (for example by a Wesseley- Moserrearrangement) The compounds of formula ll may be readily cyclized, forexample by heating under non-basic conditions. It is preferred to carryout the cyclization reaction in a non-reactive solvent such as ethanolor dioxan. It is also preferred to carry out cyclization in the presenceof a cyclization catalyst, ideally an acid cyclization catalyst such asa polyphosphoric acid, sulphuric acid, hydrochloric acid, acetic acid ormixtures thereof. When a compound is used wherein M is in alkyl group,simultaneous cyclization and dealkylation may be achieved by the use ofhydroiodic or hydrobromic acid as the cyclization catalyst.

Cyclization may be carried out at from ambient temperature to about C.,for example by heating the reaction mixture on a steam bath and, wherethe nature of the reaction medium permits it, under atmospheric reflux.

As indicated earlier, the group R" in the compound of Formula II is anOH group, or a group which is convertible to an OH group. Suchconversion may have already occurred in the cyclization of the compoundor may have taken place prior to cyclization. However,

, where this is not the case, such conversion may be The compounds ofFormula [I may themselves be I prepared by a number of methods. Forexample, an acylbenzene of the formula:

V Br

' (wherein R has the value given above and M is hydrogen, an alkalimetal cation or an alkyl group, such as a lower alkyl group, e.g., amethyl, ethyl, propyl or pentyl group), may be condensed with a compoundof the formula R CZCZR wherein R and R may be the same or different, onebeing a group reactive with an hydrogen in the CO--CH,,R group of theacylbenzene, the other being an R" group, and each Z is a carbonyloxygen or one is an (Hal), group wherein Hal is halogen. Suitable groupswhich react with a --CO- CH R group include alkoxyl, amino, alkyl amino,substituted amino or substituted alkyl amino groups. It will beappreciated that these groups include groups which are also convertibleto OH groups. Where R and/or R is an amino or substituted amino group,the nitrogen atom may carry groups E and F wherein E and/or F ishydrogen, a lower alkyl, a substituted or unsubstituted aryl, alkaryl orhaloaryl group. In the case where the nitrogen carries only one group Bor F, the substituent may be linked to the nitrogen through a sulphuratom or an -SO- or SO; group. Examples of suitable compounds for presentuse include those of the general formulas R OOCCOOR,, (wherein each R,is an alkyl group, such as methyl, ethyl, propyl, butyl group, or pentylgroup; an alkaryl group such as a benzyl group; or an alkenyl group suchas an allyl group), and R 0- C(Hal) COOR (wherein Hal is halogen,preferably chlorine or bromine). Preferred compounds of formula RCZ-CZRfor present include diethyloxalate, ethyl ethoxydichloroacetate,ethyl oxamate, ethyl oxalylanilide and ethyl oxalyl-p-toluenesulphonamide.

The condensation of the acylbenzene V with the I compound of formulaR,CZ--CZR may be carried out merely by mixing the reactants together andheating, if desired, to a temperature of from 25 to 150 C., preferablyabout 70 to 80 C. In the case of the oxalate esters, the reaction isdesirably carried out in the presence of a condensation agent. Suitableagents include for example, metal alkoxides, such as sodium ethoxide,sodium hydride, sodamide or metallic sodium. The condensation agent maybe formed in situ, for example by the use of ethanol as the reactionmedium and the addition of metallic sodium. In some cases the alkalimetal salt of the compound of Formula V (that is when M is alkali metal)may act as part of the condensation agent required. Where a substituteddihaloacetate is used, it is preferred to carry out the reaction in thepresence of a finely divided metal catalyst, such as finely dividedplatinum group metal.

lfdesired, the reaction may be carried out in an inert solvent ordiluent medium, such as diethyl ether, dioxan, ethanol, benzene,toluene, tetrahydrofuran, or mixtures thereof.

The reactants are conveniently employed in substantially stoichiometricproportions. If desired, an excess of either may be employed, forexample in from to 300 molar percent excess. When used, the condensationagent is desirably used in from 200 to 750 molar percent based on theamount of the acylbenzene of formula V used, preferably from 200 to 500molar percent.

It will be appreciated that the condensation reaction is desirablycarried out under substantially anhydrous conditions, that is in theabsence of initial or added water.

The reaction mixture of the above reaction will usually contain thecompound of formula II, or a precursor thereof, though in some casescyclization of the product to the compound of formula I, or a salt orderivative thereof, may take place spontaneously. Cyclization of thecompound of formula II may also be achieved in situ by acidifying thereaction mixture. It is usually preferred to recover the compound offormula II from the reaction mixture and to cyclize it in the presenceof a cyclization agent under substantially anhydrous conditions asdescribed above. The compound may be recovered from the crude reactionmixture wherein it was prepared by conventional techniques. Thus, forexample, the reaction mixture may be treated with ether to precipitatethe intermediate, if this precipitation had not already been achieved bythe use of ether as the reaction medium. The precipitate, after anyfurther washing with ether, may be dissolved in water and acidified toyield the compound of formula which usually separates out and may berecovered by, for example, filtration, centrifuging, or by extractionwith a suitable solvent such as chloroform or ethyl acetate andevaporation of the solvent. It may be preferred to omit the etherprecipitation step and merely acidify the reaction mixture and recoverthe product by solvent extraction.

The compound of formula II may also be prepared by the reaction of anacylbenzene offormula V wherein M is hydrogen or an alkali-metal cationwith a dicarbonyl compound of formula R COCOR wherein R and R have thevalues given above, except that one or both of R and R are halogen.Suitable dicarbonyl compounds for use in this case includeoxalylchloride and compounds wherein R, is chlorine or bromine and R isOH, alkoxy (e.g., methoxy or ethoxy) NH phenylamino or a p-toluenesulphonyl-amino group. The reaction using these halo compounds may becarried out in a manner similar to that described in relation to the useof the other compounds R CZCZR except that an acidbinding agent is usedin place of the condensation agent and that the use of an anhydrousorganic solvent is desirable. Suitable acid-binding agents includealkalis,

such as sodium or potassium carbonate, sodium, sodamide and alkali metalalkoxides; and organic amines such as pyridine or triethylamine. Theacid-binding agent is present in at least the theoreticallystoichiometric amount to bind all the halogen in the dicarbonylcompound. It may be desired to use an excess of acid-binding agent, and,if desired, the acidbinding agent may be added to the reaction mixturein a series of additions over a period of time. In some cases theacid-binding agent may be used as the reaction medium. The reactionmixture from this process will usually contain the intermediate productof the formula B COCHzR;

B;- OCOCOR" or a precursor or derivative thereof, though in some casesrearrangement of this intermediate to yield the compound of formula 11may have occurred spontaneously. Rearrangement of the intermediate mayalso be achieved in situ by the addition of an alkali and heating.However it is usually preferred to recover the intermediate product fromthe reaction mixture and rearrange it, after any purification that maybe desired, in a separate reaction step. The recovery and purificationof the intermediate product may be achieved by conventional methods.

Rearrangement of the intermediate product may be achieved by heating thecrude, or purified, recovered material under non-acidic conditions andpreferably in an inert solvent or diluent medium such as benzene,dioxan, anisole or the like. The non-acidic conditions may be achievedby the presence of a base, such as pyridine and potassium hydroxide ormonoethylamine, or of an alkali such as sodium carbonate or potassiumcarbonate, sodium hydride, sodium alkoxides e.g. sodium methoxide, ormetallic sodium. If desired, the rearrangement may be carried out underthe influence of heat, for example at from ambient temperature to 100C., e.g., by heating on a steam bath and, where the reaction mixturepermits it, under atmospheric reflux. Preferably the rearrangement iscarried out under anhydrous conditions i.e. in the absence ofappreciable amounts of initial or added water. The amount of alkalipresent may be from 100 to 1,000 molar percent, based on the amount ofthe intermediate product being rearranged and may, if desired, be addedin a single addition or in a series of additions over a period of time.

The compound of Formula II or a derivative or precursor thereof, may berecovered from the reaction mixture in which it was formed byconventional methods with, if necessary, conversion of the R" group intoa more desired substituent.

In a further process for preparing the compounds of formula II, anappropriately substituted salicylic acid or ester thereof is reactedwith a compound of the formula CH CO COOR wherein R, has the valuesgiven above. The reaction is desirably carried out in an inert mediumsuch as ethanol, anisole, benzene or dioxan and it is preferred toemploy a condensation agent such as an alkali metal alkoxide (e.g.,sodium ethoxide), sodamide, sodium hydride or metallic sodium.

The compounds of Formula Ill may be cyclized by treating the compoundwith a cyclization agent at ambient temperature or above. Suitablecyclizing agents include dehydrating agents such as phosphoruspentoxide, polyphosphoric acid, sulphuric acid, chlorsulphonic acid andother Lewis acids. In certain cases it is also possible to use glacialacetic acid containing a small amount of hydrochloric or hydrobromicacid. It will be appreciated that, since cyclization is achieved inthese cases by the use of dehydrating agents, the presence of added orinitial water in the reaction mixture is undesirable. It is usuallypreferred to subject the compounds of Formula [II to an initial dryingstep and to carry out the cyclization reaction under substantiallyanhydrous conditions.

Alternatively, cyclization may be achieved by con verting the freecarboxyl groups of the compound of Formula III into acyl chloridegroups, for example, by treatment with PCl or PCl and subjecting theresultant acyl chloride to an internal Friedel Crafts reaction.

The compounds of Formula III when R is hydrogen may be obtained by thereaction of the phenol of formula:

(wherein M is hydrogen or an alkali metal cation) with an acetylenedicarboxylic acid or ester thereof under alkaline conditions to producea product which, upon hydrolysis, yields the compound of Formula III.The acetylene dicarboxylic acid esters may be derived from alcoholshaving from one to 10 carbon atoms. However, since the ester moiety isto be eliminated, it is preferred to use simple esters derived forexample, from methyl, ethyl, propyl, or butyl alcohols. It is preferredthat both carboxylic acid groups on the acetylene dicarboxylic acid beesterified. In this process the ester and phenol are reacted, preferablyin approximately stoichiometric amounts, under alkaline conditions.These may be achieved by the presence of an organic base such as benzyltrimethyl ammonium hydroxide, or of an alkali metal hydroxide. However,it is convenient to have the alkali present in theform of an alkalimetal salt, especially the sodium salt, of the reactant phenol, such asalt being considered as free phenol when assessing the amount of phenolpresent in the reaction mixture. Where this is done, the alkali metalphenate may conveniently be made in situ in the reaction mixture by theaddition of metallic sodium. The alkali is believed to act catalyticallyand it is possible to use less than molar percent thereof based on thephenol present. We prefer to use substantially 10 molar percent. It willbe appreciated that the reaction, especially where the alkali metalphenate is formed in situ, is desirably carried out under substantiallyanhydrous conditions. It is also preferred to carry out the reaction ina solvent or diluent medium. Suitable media included, for example,excess of the reactant phenol, diphenyl ether, dioxan and anisole. Thesemedia have the advantage that the reaction may be carried out atelevated temperatures at atmospheric pressure. It is generally preferredto carry out the reaction at temperatures of from 50 to 100 C.

In place of the acetylene dicarboxylic acid ester used in the aboveprocess for the preparation of the compound of Formula III, an ester ofa mono-halofumaric acid, or a precursor thereof may be used, i.e.,esters of acids of the general formula wherein R is halogen and R is anR, group when R and R together form a carbon to carbon bond; or, any twoof R R R and R are halogen, one of the other two is hydrogen and thesecond is an R, group. In this case the reaction is not an additionreaction but a condensation reaction which involves at some stage theelimination of the elements of a halogen acid from between the phenoland the halofumeric ester. This acid must be eliminated from the systemand the reaction is therefore carried out in the presence of at leastsufficient of an acid-binding agent to eliminate the elements of thehalogen acid which will be formed during the overall process. Theelements of the halogen acid are not necessarily eliminated in one step,but may be eliminated firstly as a proton and then as a halogen anion.The term acid-binding agent is therefore used in this context to denoteboth conventional acid-binding agents, such as pyridine andtriethylamine, and materials which eliminate for example,'first thehydrogen from the phenol (to form a phenate salt) and then are displacedfrom the phenate salt to form a salt with the halogen of the halofumaricacid ester: Apart from the use of a different acid ester reactant aridthe presence of the acid-binding agent, the process may be. carried outin similar manner to that when an acetylene dicarboxylic acid ester isused. Since the acid-binding agent is usually also a strong alkali,there is generally no need to provide a separate strong alkali in thereaction mixture. As will be appreciated from the general formula forthe acids which may be used to react with the phenol, the use of themonohalofumaric acid or precursors thereof permits the introduction ofan R, group into the molecule.

As indicated above, it is also possible to use compounds which yield thedesired halofumaric acid esters under the conditions of the reactionwith the phenol. Such other compounds or precursors, include halomaleicacid esters and dihalosuccinic acid esters. When precursors are used, itmay be necessary to provide extra alkali to ensure conversion of theprecursor to the desired halofumaric acid ester. Such alkali may bemerely an excess of the acid-binding agent.

The products obtained from the reactions outlined immediately aboveusually contain the compounds of Formula III in the form of theiresters. The compounds of Formula III may be recovered from theseproducts by acidification of the reaction mixture; subsequent hydrolysisof the esters by boiling with alkali and acidification to liberate thefree acid, removal of organic solvent or diluent medium (if any) andextraction of the aqueous solution with, for example, ether which maythereafter be evaporated. The solvent extraction of the acid may becarried out as indicated, or may occur after hydrolysis of the ester ofcompound III if desired. The product may, if necessary, be subjected tofurther purification, for example by extracting the ethereal solutionwith sodium bicarbonate and then precipitating the acid of Formula IIIby addition of dilute sulphuric acid.

The compounds of Formula IV may be cyclized by treatment with an alkalior organic base in a suitable inert solvent to give theZ-carboxychromanone deriva tive. This may subsequently be converted intothe 2- carboxychromone derivative by heating with selenium dioxide orother suitable dehydrogenation agents such as palladium black in aninert solvent as is detailed below. Simultaneous oxidation andcyclization to the desired 2-carboxychromone derivative may be broughtabout by the introduction of a suitable oxidant into the cyclizationstage (e.g., selenium dioxide in an inert solvent usingbenzyltrimethylammonium hydroxide as the cyclizing base).

Where non-oxidizing conditions are used for the cyclization step, theproduct will be the analogous chromanone compound from which the desiredCOOH The compounds of Formula IV may be prepared by reacting anacylbenzene of Formula V wherein M is hydrogen or an alkali-metal cationwith glyoxalic acid or an ester thereof in the presence of a base (e.g.,aqueous sodium hydroxide) or a mineral acid. A water miscible solvent,e.g., alcohol, may be added to facilitate the reaction.

Alternatively a phenol of formula VI wherein M is hydrogen is heated ata temperature of, for example, 25 to C. with maleic anhydride in asolvent or diluent medium, such as nitrobenzene or carbon disulphide, inthe presence of a Lewis acid such as an excess of aluminum trichloride.The complex which is produced by this process may then be decomposedwith a dilute mineral acid, such as hydrochloric acid, and the solventremoved, for example by distillation. The residue, which contains thecompound of Formula IV wherein R" is OH, may be recovered usingconventional techniques and then purified by, for example,recrystallization. However, as indicated below the reaction may proceedto give a 2-carboxychromanone directly without isolation of anintermediate.

In the processes outlined above, we believe that the compounds II to IVare all necessary intermediates in the conversion of the variousstarting materials to the compounds of Formula I. However, in many casesthe intermediates are formed under those conditions required to achievecyclization and therefore exist only transitorily. While, for clarity,these processes have been described as if the compounds II to IV werenecessarily isolated prior to eyclization, the invention embraces thoseprocesses wherein the intermediate undergoes eyclization withoutseparation or isolation from the reaction mixture in which it has beenprepared.

As indicated above, the desired ring may also be formed from an alreadypresent chromone ring, i.e., from a compound of formula VII wherein V isa group which is convertible to a COOR group. Examples of suitable Vgroups include nitrile and ester groups which may be hydrolized to acarboxylic acid group; alkyl or substituted alkyl groups such as methyl,hydroxymethyl, halomethyl (e.g., chloromethyl, bromomethyl,dichloromethyl, trichloromethyl), acyl groups such as forrnyl or acetylgroups, and alkenyl and aryl alkenyl groups such as vinyl,w-trichloromethylvinyl and styryl groups, all of which are groupsoxidizable or hydrolyzable to a carboxylic acid group. The conversion ofthe V group to a COOH group or derivative thereof may be achieved usingany of the known methods.

The compounds of Formula VII may be prepared by a variety of methods,many of which are closely analogous to the processes described above forthe preparation and cyclization of the compounds of Formula II to IVexcept that in place of the starting materials II, III and IV, compoundsof the formulas VIII 1 1 B2- C O-AIH-C O--V B3 ORz and are used and thatthe final product requires conversion of the V group to the COOl-l groupor derivation thereof. Such analogous processes may together by broadlydescribed as a process for preparing a compound of Formula I byconversion of a compound of the formula (wherein A and A are the pairsof groups COCHR,COD and OM; H and 0C(D)= CR COOH; or COCR,=CHD and OMrespectively wherein D is a COOR, group or a group V convertiblethereto, M is B, an alkali-metal cation or an alkyl group, M is H or analkali metal cation and R and R have the values given above; oneadjacent pair of the substituents B 13,, B, and B. is the groups A, andA,, which may have the values given above for A and A or may be the pairof groups A, and A and the other two of the groups B,, 8,, Bor B arehydrogen or substituents other than hydrogen) during which cyclizationof the groups A, and A and, if necessary, A, and A takes place.

Thus the compounds of Formula Vll may be prepared by cyclizing acompound of Formula Vlll under the conditions described above for theeyclization of the compound of Formula II. In some instances eyclizationmay occur spontaneously.

The compounds of Formula VIII may themselves be prepared by condensingan acylbenzene of Formula V with a compound of formula VCOR,, wherein Vhas the values given above and R, is a group reactive with a hydrogen inthe ---COCI-I,R group of the acylbenzene. Suitable compounds VCOR,include esters of substituted or unsubstituted acetic, acrylic andcinnamic acids, and the like, and amides or substituted amides. Thecondensation may be achieved by the method outlined earlier for theproduction of the compounds of formula II from the acylbenzene V and thecompounds R, CZCZR The compounds VIII may also be prepared from theacylbenzene V and the compounds VCOR wherein R is halogen via, ifnecessary, the rearrangement of a compound of the formula:

COCH:R

-OCOV I Ba alkyl acetate, i.e., the compound VCOR wherein V is a methylgroup and R is an alkoxy group, with an acylbenzene V under thecondensation conditions outlined above for the preparation of compoundII.

The 2-styryl compound, that is the compound of Formula VIII wherein V ismay be prepared from the acylbenzene V by reaction with sodium cinnamateand cinnamic anhydride or by reaction with a cinnamoyl halide, e.g.,cinnamoyl chloride, in the presence of an acid-binding agent to yieldthe cinnamate ester of the acylbenzene, followed by rearrangement with abase, e.g., potassium carbonate, in the presence of an inert solventsuch as toluene or benzene, to give a l, 3-diketone of the formula:

wherein Ar denotes a benzene ring.

From these examples of the preparation of the compounds of Formula VIIIit will be appreciated that certain of the processes for preparing thecompounds of Formulas II and VIII may together be broadly described asprocesses wherein an acylbenzene of Formula V is reacted with a compoundwherein R is a group reactive with an hydrogen in the -CCI-I R group ofthe acylbenzene, each Z is 0 or one may be a (Hal), group, n is l or 2and when n is 1, W is a D group Le. a COOR; group or a group Vconvertible thereto and when n is 2, W is an R" group, i.e., an OH groupor a group convertible thereto.

The compounds of Formula IX may be prepared by the reaction of a phenolof Formula VI with a substituted acetylene monocarboxylic acid, or esterin manner similar to that used to prepare the compounds of Formula Illabove. The acetylene monocarboxylic acids, or esters thereof, forpresent use have the general formula VC= C-COOR, wherein V and R, havethe values given above. It is preferred that R, be a lower alkyl groupsuch as a methyl or ethyl group. It is also possible to use precursorsof acetylene monocarboxylic acids or esters, for example themono-halo-ethylenic and dihalo-ethane analogues thereof.

The compounds of formula IX may be cyclized in a manner similar to thatemployed with the compounds of Formula III. As with the compounds ofFormula II and VIII, the preparation of the compounds of Formula III andIX may together be broadly described as a process wherein a phenol ofFormula VI is reacted with a compound of the formula wherein R R R R Rand D have the values given above and also the further value that whenR, and R together form a carbon to carbon bond, R and R may also form acarbon to carbon bond.

The compounds of FormulaX may also be prepared and cyclized in a mannersimilar to that used to prepare and cyclize the compound of Formula IV.Thus, an acylbenzene of Formula V may be reacted with an aldehyde of theformula Ol-ICV, for example cinnamaldehyde, under substantially the sameconditions as are used to prepare the compound of Formula IV fromglyoxallic acid. However, it may be preferred to employ acylbenzenes offormula V wherein M is an alkyl group and to dealkylate the reactionproduct to obtain the compound of Formula X.

As with the other intermediate compounds, certain routes for thepreparation of the compounds of Fonnu' la IV and X may together bebroadly described as comprising the reaction of an acylbenzene ofFormula V with a compound of the formula OHCD wherein D has the valuesgiven above.

In addition to producing the compounds of formula VII by the methodsoutlined above, a number of other methods may be readily devised whichdo not necessarily pass through the intermediate compounds VIII, IX orX. Thus, the 2-formyl compound may be prepared by the reaction of anacylbenzene of formula V with a substituted acetic acid or ester thereofof the formula (R O),CI-I-COOR,, for example ethyl diethoxy acetate. Inthis case an acetal compound is produced as an intermediate, which maybe hydrolized with, for example, a dilute mineral acid to yield thedesired CI-IO group. Other routes which may be specified include: thecondensation of a diketene with an appropriate enamine; the condensationof an alkyl alkoxalylacetate with an appropriate phenol or resorcinol inthe presence of phosphorus pentoxide.

In addition to the direct conversion of a compound of Formula VII intothe desired compound of Formula I, the V group in compounds of FormulaVII may be converted in known manner from one form of substituent intoanother more preferred substituent.

Thus, the compound of Formula VII wherein V is a methyl group alsoserves as an intermediate in the preparation of a number of otheroxidizable derivatives. For example, the methyl group may be convertedinto the corresponding 2-halo-methyl compound, e.g., by reaction withhydrogen chloride and manganese dioxide in boiling acetic acid toproduce the 2- chloromethyl compound; or by reaction with bromine inacetic acid to yield the Z-bromomethyl compound. The 2-halomethylcompound may be oxidized to the corresponding 2-carboxylic acid using,for example, chromium trioxide as oxidizing agent in the presence ofacetic acid.

The Z-methyl compound may also be reacted with pnitrosodimethylanilineand the reaction product hydrolyzed with dilute mineral acid to give thecorresponding 2-formyl compound which may be oxidized to thecorresponding Z-carboxylic acid using, for example, chromium trioxide asreagent.

Condensation of the 2-methyl compound with a benzaldehyde in thepresence of condensation catalyst gives the 2-styryl compound which maybe oxidized to the corresponding 2-carboxy1ic acid using, for example,potassium permanganate. The 2-formyl compound may also serve as astarting point for the preparation of the 2-cyano compound. Thus, the2-formyl compound may be reacted with hydroxylamine to yield the2-oximino compound which may, after dehydration to give the 2-cyanocompound, be hydrolyzed to the 2-carboxylic acid or amide thereof, underacid conditions.

As stated earlier the compounds of Formula I may also be prepared byconversion of a chain CO Cl-IR,Cl-I(D)O to the desired CO-CR =C(COOH)Ochain. This conversion may go via a compound of Formula VII when thegroup D is a group V, or may procede directly to the compound of formulaI or a derivative thereof. Thus, the compounds of Formula I may also beprepared from corresponding chromanone compounds by dehydrogenationfollowed, or preceded, by oxidation or hydrolysis of any substituent inthe 2-position if this is necessary. The dehydrogenation may be effectedby, for example, the use of selenium dioxide, palladium black orchloranil. Alternatively, dehydrogenation may be carried out bybromination followed by dehydrobromination. Thus, the chromanone may bebrominated using N- bromosuccinimide in an inert solvent or by treatmentwith pyridinium perbromide in an inert solvent such as chloroform in thepresence of a free radical catalyst such as benzoyl peroxide, to yieldthe 3-bromo derivative which may be subsequently dehydrobrominated. Thechromanones themselves may be obtained by the action of an B-substitutedB-chloropropionic acid or derivative thereof on resorcinol in thepresence of a basic reagent followed by conversion of the acid functionto the acid chloride and treatment with aluminum chloride in thepresence of a suitable solvent (e.g., nitrobenzene); or by the action ofa phenol on a B-substituted acrylonitrile, e.g., propenylnitrile withsubsequent hydrolysis and cyclization of the product. As indicatedabove, cyclization of the intermediates IV and X may lead to theproduction of a corresponding chromanone compound, which may then beconverted as outlined above to the desired chromone compound.

In addition to the above outlined methods for preparing the compounds ofFormula I via the intermediates II to IV and VII to X, other methods maybe devised which do not necessarily produce any of these intermediates.Thus, an acetylhalide, acetic anhydride or acetic acid may be condensedwith an oxalate ester of the type R OOC-COOR wherein R is an aryl groupand R is an alkyl or an aryl group, the condensation being carried outin the presence of a Lewis acid. The oxalate ester may itself beobtained by the esterification of a phenol of Formula VI-with theappropriate oxalyl halide. Alternatively the compounds of Formula I maybe obtained by reacting a phenol of Formula VI with ethyl ethoxalylacetate and subsequently cyclizing the product, if necessary, e.g., byheating in a solvent medium. In a further process a 2-carboxy-pyrone ofthe COOR2 is reacted with a furan of the formula which may be converted,for example by dehydration, to the compound.

CODE:

As stated earlier, the desired rings may be introduced in separate stepsor in the same step. Where they are both to be introduced together, thetwo pairs of groups A and A will have the same values, appropriate tothe method used to introduce the rings. Thus, where condensation with anacylbenzene forms one of the steps required, one group in each pair willbe a COCI-I,R, group and the other will be an OM group.

From the above examples of the conversion of the starting materials B:At

into the desired B] O I] B l RI Br COOH O compounds, it will be seenthat many of the routes may be together broadly described as theconversion of compounds wherein A, and A together form the groups OM andH, D or COD; H and OCD=CRCOOR OCOCOR" and H or COCH R, respectivelywherein D is a group CH R,, R CI-IR,COD or CR,=CHD and R", R,, R D and Mhave the values given above; or wherein A, and A together form thechains CO-CR,=C(D)O or COCHR,--CH(D)O; 13,, B B and B having the valuesset out above.

The processes outlined above may produce the free acids of Formula I ormay yield derivatives thereof. It is also within the scope of thepresent invention to treat the product of any of the above processes,after any isolation and purification steps that may be desired, in orderto liberate the freeacid therefrom or to convert one form of derivativeinto another. The methods used to free the acid, convert one derivativeinto another and to isolate and purify any product'ma y bethoseconventionally used.

Furthermore, it is also within the scope of this invention to introducethe substitutents P, Q, R, T, P, Q, R, and T after formation of one orboth the COOH ring or rings. Such shielding or blocking groups include,for example, amino, substituted amino e.g., acylated amino, carboxyl,S0,,I-I, tert. butyl, cyano or nitro groups. These groups may be removedafter introduction of the ring or rings to leave unsubstituted positionswhich may, if desired, thereafter be substituted.

Certain of the intermediates formed in the production of the compoundsof formula I are, we believe, novel. The invention therefore alsoprovides as novel compounds, compounds of the general Formulas II, III,IV, VII, VIII, IX and X set out above, except those wherein A, and A,are the pairs of groups OM and H or COCH,R,; notably those compoundswherein one pair of the groups A, and A, forms the chain COCR,= C(D)O-or -C0-CHR,-CH(D)O. Preferred compounds are those wherein each pair ofgroups A, and A are the same, other than a chain --COCR,= C(COOI-I)O.

The invention will be illustrated by the following Examples in which allparts and percentages are by weight unless otherwise stated:

EXAMPLE I 4, l0-Dioxo-5-methoxy-2,8-dicarboxy-4H, l OH-benzo(l,2-b:-3,4-b' )dipyran a. 4, I O-Dioxo-5-methoxy-2,8-dicarboxy-4H 1 0H-benzo l,2,-b:-3,4-b) dipyran, monohydrate To a stirred solution ofsodium ethoxide in ethanol, prepared from 3.04 parts of sodium and 40parts of ethanol, was added a slurry of 3.7 parts of2,4-diacetyl-5methoxyresorcinol and 12.05 parts of diethyl oxalate in 20parts of ethanol and 50 parts of diethyl ether. The mixture was stirredand heated under reflux for 4 hours.

Diethyl ether and water were added, and the aqueous layer was separatedand acidified with dilute hydrochloric acid. The aqueous solution wasextracted with ethyl acetate dried over sodium sulphate, filtered andevaporated to dryness to leave a brown oil.

This oil was dissolved in boiling ethanol and 0.5 parts of concentratedhydrochloric acid were added. The solution was heated under reflux for10 minutes and the solvent was then removed under reduced pressure toleave a brown oil.

This oil was triturated with ether to give a solid which was shown bythin layer chromatography to be a mixture of acid and ester. The solidwas heated in aqueous sodium bicarbonate solution until it had alldissolved. This solution was cooled and acidified with dilutehydrochloric acid to give 0.96 parts of 4, IO-dioxo-S-methoxy-2,8-dicarboxy-4I-I,IOI-I-benzo( 1,2-b:-3,4-b) dipyran,monohydrate as a pale brown solid, melting point 262'3 C.(d).

Analysis:

C 51.7% H3.02% C5 I 5% H2.86%

b. 4,10-Dioxo-5-methoxy-2,8-dicarboxy-4I-I,10H-

benzo (I,2-b:-3,4-b') dipyran, disodium salt A solution of 0.83 parts of4, IO-dioxo-S-rhethoxy- 2,8-dicarboxy-4I-I, l OI-I-benzo (l,2-b: 3 ,4-bdipyran monohydrate and 0.4 parts of sodium bicarbonate in 50 parts ofwater was freezedried to give 0.83 parts of4,10-dioxo-5-methoxy-2,8-dicarboxy-4I-I, IOI-I-benzo (l,2-b:3,4-b')dipyran disodium salt as a pale yellow solid.

EXAMPLE 2 4, l 0-Dioxo-2,8-dicarboxy-5hydroxy-4H, l OH-benzo (l,2,-b:3,4-b') dipyran a. 4, l 0-Dioxo-2,8-dicarboxy-5 hydroxy-4H I OH benzo I,2-b: 3,4-b)dipyran monohydrate.

A solution of 0.55 parts of4,I0-dioxo-2,8-dicarboxy-5-methoxy-4H,IOI-I-benzo (1,2-b: 3,4-b) dipyranmonohydrate (Prepared as in Example I) in a mixture of 7 parts ofhydrogen bromideacetic acid (45% w/v) and 7 parts of glacial acetic acidwas refluxed for 1% hours. During this time, a solid separated out ofthe reaction mixture. The mixture was poured into 200 parts of water andthe solid precipitate was filtered off.

The solid was dissolved in aqueous bicarbonate solution and the solutiontreated with charcoal and filtered. Acidification of the bicarbonatesolution with dilute hydrochloric acid gave 0.3 parts of 4,l-dioxo-2,8-dicarboxy--hydroxy-4H,l0H-benzo (1,2-b: 3,4-b') dipyran monohydrate as apink solid, melting point 300-2 C. (d).

Analysis:

Found: c, 49.8% H, 2.14% C H.O.'H,O requires: C, 50.01% H, 2.4%

b. 4,10-Dioxo-2,8-dicarboxy-5-hydroxy-4H,10H-

benzo 1,2-b: 3,4-b') dipyran disodium salt A solution of 0.238 parts of4,l0-dioxo-2,8-dicarboxy-5-hydroxy-4H,lOH-benzo (1,2-b: 3,4-b') dipyranmonohydrate and 0.1 l3 parts of sodium bicarbonate in 30 parts of waterwas freezedried to give 0.23 parts of4,l0-dioxo-2,8-dicarboxy-5-hydroxy-4H,lOH-benzo (1,2-b: 3,4-b') dipyrandisodium salt as a buff colored solid.

EXAMPLE 3 4, lO-Dioxo-S-methyl-Z,8-dicarboxy-4H, IOH-benzo(l,2-b:3,4-b') dipyran To a solution of 3.1 parts of anhydrous orcinolin 50 parts of anhydrous dioxan were added 0.23 parts of sodium. Themixture was stirred and heated until the sodium had dissolved. Thestirred solution was then treated dropwise with a solution of 7.5 partsof dimethyl acetylene dicarboxylate in 20 parts of anhydrous dioxan.After stirring and heating on a steambath for 15 minutes, the mixturewas cooled and acidified with 9 parts of 10% w/v sulphuric acidsolution. it was then treated with 25 parts of 25% w/v sodium hydroxidesolution; heated on steam-bath for one hour; cooled; acidified with 10%w/v sulphuric acid solution; and the dioxan was then distilled off. Themixture was extracted with ether and the ether evaporated to leave ayellow solid which was crystallized from water to give 1.0 parts oforcinol di(trans, 1,2-dicarboxy vinyl) ether, melting point, 260-l C.

Analysis Found C, 50.92% H, 3.59% C H O requires C, 51.15% H,3.4l%

The structure was confirmed by nuclear magnetic resonance spectrum.

A mixture of 0.5 parts of orcinol di(trans, l,2-dicarboxy vinyl) etherand parts of polyphosphoric acid was stirred and heated at l1020 for 3hours. The mixture was cooled and diluted with ice-water. Thesupernatant liquid was decanted off and the precipitated solid wasfiltered off, washed with water and dried in the oven to leave 0.3 partsof 4,l0-dioxo-5-methyl-2,8- dicarboxy-4H, l0H-benzo (1,2-b; 3,4-b')dipyran sesquihydrate, melting point, 285-6 C. (Decomp).

Analysis Found: C, 52.22% H, 3.02% C H,O,-l%H,O requires C, 52.49% H,3.2%

The material was shown to be identical with the free acid obtained byreaction of diethyloxalate and 2,4- diacetylresorcinol using the methodof Example 1 by comparison of melting points and infra-red spectra.

2,8-Dicarboxy-4, l 0-dioxo-5-methoxy-4l-l, l OH-benzo (1,2-b: 3,4-b')dipyran A mixture of 5-methoxy-2,4-diacetylresorcinol (20 parts) andethyl ethoxydichloracetate (52 parts) was heated at 150 to 170 C. for 5hours. After evaporating off any volatile material under reducedpressure, a mixture was obtained which was hydrolyzed by dissolving inglacial acetic acid containing 17% of concentrated hydrochloric acid(500 parts total) and refluxing for 4 hours. After cooling, a solid wasobtained. This solid was filtered off, washed well with water andpurified by dissolving in aqueous sodium bicarbonate, treating the hotsolution with charcoal, filtering and precipitating with concentratedhydrochloric acid. The product, 2,8- dicarboxy-4,l0-dioxo-5 methoxy-4H,l0H-benzo (1,2- b; 3,4-b) dipyran monohydrate, was shown to beidentical with the product of Example la.

EXAMPLE 5 2,8-Dicarboxy-4 l 0-dioxo-5 -m ethoxy-4H 10H -benzo s 3,4-b')dipyran monohydrate A solution of 5-methoxy-2,4-diacetylresorcinol (1part) and ethyl N-toluene-p-sulphonyloxamate (10 parts) in parts byvolume of dry ethanol and 10 parts by volume of dioxan, was added to asolution .of 1.3 parts of sodium in parts by volume of ethanol. Theresultant mixture was heated under reflux for 20 hours. After coolingthe mixture, a large excess of ether (500 parts) was added and themixture was extracted with water. The aqueous extract was acidified andextracted into chloroform and filtered to remove by-product bis (N,N'toluene -p-sulphonyl) oxamide. The chloroform solution was dried andevaporated to dryness, yielding a sticky solid which was washed severaltimes with ether, the ethereal extracts being separated by decantation,to leave a further amount of his (N, N' toluene-psulphonyl) oxamide. Theethereal extracts on evaporation gave an oil which was dissolved inethanol (20 parts) containing a few drops of concentrated hydrochloricacid. This solution was refluxed for 15 minutes and the solvent removedin vacuo to yield a brown oil.

Thin layer chromatography showed that this oil was probably a mixture ofthe desired acid and its ester. The mixture was therefore hydrolyzedwith aqueous sodium bicarbonate. Heating of the hydrolysis mixture wascontinued until complete solution was achieved. The solution was thentreated with charcoal, filtered and acidified to yield2,8-dicarboxy-4,lO-dioxo-S-methoxy- 4H,l0H-benzo (1,2-b: 3,4-b') dipyranmonohydrate which was shown to be identical to the product obtained inExample la.

EXAMPLE 6 2,3-Dicarboxy-4, 10-dioxo-5-methoxy-4H, lOH-benzo 3 ,4-b')dipyran monohydrate Ethyl oxalylchloride (8parts) was added slowly to amixture of 2,4-diacetyl-5-methoxyresorcinol (2.5 parts) and anhydrouspyridine( parts) cooled in ice. The mixture was kept at room temperaturefor 24 hours and then heated for 30 minutes on a steam bath. Aftercooling and pouring onto a mixture of ice and hydrochloric acid, an oilwas obtained which was extracted with chloroform, washed and thechloroform solution then dried over sodium sulphate. After filtrationand removal of the solvent, the residue was crystallized from ethanol togive 2,8-dicarboxy-4,l0-dioxo-5- methoxy -4H, lOH-benzo (1,2-b: 3,4-b')dipyran monohydrate which was shown to be identical with the product ofExample la.

EXAMPLE 7 2,8-Dicarboxy-4, l0-dioxo-5-methoxy-4H, 10H-benz0 (1,2-b:

3,4-b') dipyran monohydrate.

A mixture of phloroglucinol monomethyl ether (2 parts) and ethylethoxalylacetate (10 parts) in diphenyl ether (30 parts) was heated for4 hours at 150 C. The reaction vessel was fitted with an air condenser,so that volatile reaction products, such as water and ethanol, couldescape from the reaction mixture. After cooling, the reaction mixturewas triturated with an excess of petroleum ether (b.p. 60-80 C.) severaltimes, to leave a sticky gum. Aqueous sodium bicarbonate was added tothis gum and the mixture heated on a steam bath until solution of thegum was achieved. Acidification of the solution gave 2,8-dicarboxy-4,IO-dioxo-S- methoxy-4H, IOH-benzo (1,2-b: 3,4-b') dipyran monohydratewhich was shown to be identical with the product of Example 1a.

EXAMPLE 8 2,8-Diethoxycarbonyl-4, l0-dioxo-4H, IOH-benzo 1,2-b:

3,4-b') dipyran Resacetophenone (7.6 parts) and dimethyl acetylenedicarboxylate parts) were mixed together and 3 drops ofbenzyltrimethylammonium hydroxide (40% aqueous solution) were added. Theresulting solution was heated on a steam bath for 1 hour and thencooled, treated with sodium hydroxide (45 parts of 25% aqueous solution)and heated on a steam bath for 3 hours. The mixture was then cooled andacidified with sulphuric acid H,SO A precipitate was slowly deposited,which was filtered off, washed with water and crushed to leave a fawnpowder. This powder was crystallized from water to give 3.5 parts of3-hydroxy- 4-acetylphenoxyfumaric acid hemi-hydrate.

Melting point 217 C. (d)

Analysis:

A mixture of this material and concentrated sulphuric acid (18 parts)was stirred until a clear solution was obtained. The solution was thenheated on a steam bath for 10 minutes, cooled and poured onto ice. Afine green precipitate was obtained which settled under gravity. Thisprecipitate was filtered off, washed with water and dried. The driedpowder was crystallized from ethanol to give 0.9 parts of 5-hydroxy-6-acetylchromone-Z-carboxylic acid, whose structure was confirmed by NMRevidence.

Found: C, 58.0% H, 3.26% C H O requires C, 58.1% H, 3.23

Melting point 262 C. (d)

This product (0.5 parts) was mixed with diethyl oxalate (5 parts byvolume) in dry ethanol (20 parts by volume) and the mixture added to asolution of sodium (0.5 parts) in dry ethanol (50 parts by volume). Theresultant solution was stirred and heated under reflux for 16 hours,cooled and poured into a large volume of ether. The mixture wasextracted several times with water and the aqueous extracts acidified.The acidified aqueous extracts were then extracted with chloroform(three 50 part lots). The chloroform extracts were washed with water,dried and evaporated to dryness leaving an oil. This oil was dissolvedin dry ethanol (20 parts) and the solution saturated with hydrogenchloride by passing a stream of dry hydrogen chloride through thesolution. This mixture was kept overnight and then refluxed for 1 hour.The ethanol was evaporated and iced water added to the residue to give asticky solid. The water was decanted and the solid crystallized fromethanol to give 2,8-diethoxycarbonyl- 4, l0-dioxo-4H, lOH-benzo (1,2-b:3,4-b') dipyran which was shown to be identical to the ester obtainedwhen 2,4-diacetylresorcinol was reacted with diethyl oxalate using theprocess of Example 1.

EXAMPLE 9 2,8-Dicarboxy-4, 6-dioxo-l0-nitro-4H, 6H-benzo (1,2-

5,4-b') dipyran Powdered aluminum chloride (15 parts) was added withstirring to a solution of 2-nitroresorcinol (3.5 parts) and maleicanhydride (5.5 parts) in ethylene dichloride (200 parts). After standingat room temperature for 20 hours, the mixture was warmed to C. for 1hour, cooled and filtered to give a yellow residue. This residue wasadded with stirring to a mixture of crushed ice (20 parts), concentratedhydrochloric acid (10 parts) and chloroform parts). The mixture wasallowed to separate into two layers. After 30, minutes the organic layerwas removed, the aqueous layer extracted with further lots of chloroformand the chloroform extracts combined with the organic layer. Thecombined organic layer was dried over sodium sulphate and the chloroformevaporated off in vacuo to give a reddish brown oil which was taken upin amyl alcohol (50 parts) and selenium dioxide (3 parts) was added. Themixture was refluxed for 18 hours. The inorganic materials were thenremoved by centrifuging and decanting. The organic layer was then steamdistilled to remove the solvent and purified by dissolution in sodiumbicarbonate, treatment with charcoal,

filtration and precipitation with concentrated hydrochloric acid to give2,8-dicarboxy-4, 6-dioxo-l0- nitro-4H, 6H-benzo (1,2-b: 5,4-b') dipyranwhich was identical to the compound obtained when 2,4-diacetyl- 6nitroresorcinol was reacted with diethyl oxalate using the method ofExample 1.

EXAMPLE l 2,8-Dicarboxy-4, 6-dioxo-l0 methyl-4H, 6H-benzo 5,4-b')dipyran 3 ,7-Diacetyl-2,8-dimethyl-4,6-dioxol O-methyl- 4H, 6H-benzo(1,2-0: 5,4-b) dipyran) A mixture of 4,6-diacetyl-2-methylresorcinolAnalysis:

Found C 67.5% H 4.56% C H O requires C 67.0% H 4.71% Melting point280285 C.

b. 2,8-Dimethyl-4,6-dioxo-l0-methyl-4H, 6H-benzo (1,2-b: 5,4-b') dipyranA mixture of 3,7-diacetyl-2,8-dimethyl-4, 6-dioxol0-methyl-4H, 6H-benzo(1,2-b: 5,4-b) dipyran (0.9 parts are prepared above), sodium carbonate(2.0 parts) and water (40 parts) was heated under atmospheric reflux for1.5 hours. The resulting solution was acidified and the precipitatedsolid was filtered off, washed with water, and crystallized from ethanolto give 2,8- dimethy1-4,6-dioxol 0-methyl-4H, 6H-benzo (1,2-b: 5,4-b')dipyran (0.5 parts) as a yellow solid. 2,8-Dicarboxy-4,6-dioxo-l0-methyl-4H, 6H-

benzo 1,2-b: 5,4-b') dipyran hemihydrate Finely divided selenium dioxide(1.2 parts) was added to a mixture of 2,8-dimethyl-4,6-dioxo-l 0-methyl-4l-i, 6H-benzo (1,2-b: 5,4-b') dipyran (1.0 part as preparedabove) and dioxan (20 parts). The resulting mixture was heated underatmospheric reflux for 8 hours. After cooling the reaction mixture, theselenium precipitate was filtered off and the solvent removed from thefiltrate by evaporation in vacuo. The solid residue was extracted withaqueous sodium bicarbonate. The extract was acidified with dilutehydrochloric acid and the precipitated solid filtered off to give2,8-dicarboxy-4,6-dioxo-l0-methyl-4H 6H- benzo (1,2-b: 5,4-b') dipyranhemihydrate. The

product had a melting point of 2924 C. and was shown to be identical tothe product obtained by the reaction of 4,6-diacetyl-2-methylresorcinolwith diethyl oxalate using the process of Example 1.

EXAMPLE l1 2,8-Dicarboxy-4,6-dioxo-10-methyl-4H, 6H-benzo (1,2-b:5,4-b') dipyran 2,8-Dimethyl-4,6-dioxo-l0-methyl-4H, 6H-benzo (1,2-b:5,4-b') dipyran A mixture of powdered sodium (2.3 parts), 4,6-

diacetyl-2 methylresorcinol (2.08 parts) and ethyl acetate parts) wasstirred and heated under gentle atmospheric reflux for 4 hours. Theresulting solution was cooled and diluted with diethyl ether ;parts). Asolid was precipitated, filtered off, and extracted with water. Theaqueous extract was acidified with dilute hydrochloric acid and an oilprecipitated. The oil was extracted into ethyl acetate. The organicsolution was dried over sodium sulphate, filtered and the solventremoved to yield an oil. This oil was heated under atmospheric refluxfor 15 minutes with ethanol (20 parts) and concentrated hydrochloricacid (0.5 parts). The solid which crystallized out from the reactionmixture on cooling was filtered off to give 2,8-dimethyl- 4,6-dioxo-l0-methyl-4H, 6H-benzo (1,2-b: 5,4- b') dipyran which wasidentical to that obtained in step b of Example 10.

b. The 2,8-dimethyl-4,6-dioxo-l0-methyl-4H, 6H-

benzo (1,2-b: 5,4-b') dipyran was oxidized to the corresponding2,8-dicarboxyl-4,6-dioxo-10- methyl-4H,6H-benzo (1,2-b: 5,4-b) dipyranhemihydrate by the method of step (c) of Example 10.

EXAMPLE 12 2,8-Dicarboxyl-4, 6-dioxol 0-methyl-4H, oH-benzo 5,4-b)dipyran a. 2,8-Distyryl-4, 6-dioxo-l0-methyl-4H, 6H-benzo (1,2-b:5,4-b') dipyran A slurry of 2,8-dimethyl-4,6-dioxo-l0-methyl-4H,6H-benzo (1,2-b: 5,4-b') dipyran (2.6 parts, prepared as in Example 10or 11) and benzaldehyde (2.12 parts) in ethanol (20 parts) was added toa stirred solution of sodium ethoxide in ethanol, which had beenprepared by dissolving sodium (0.46 parts) in ethanol (20 parts). Themixture was stirred and heated under atmospheric reflux for 4 hours andthen left to stand at room temperature for 18 hours. The supernatantliquor was decanted from the brown oil which had precipitated. The oilwas washed by trituration with ether and not purified further, to yield2,8-distyryl-4,6-dioxo-l0- methyl-4l-l, GH-benzo (1,2-b: 5,4-b')dipyran. 2,8-Dicarboxyl-4, 6-dioxo-l0-methyl-4H, 6H-

benzo (1,2-b: 5,4-b) dipyran hemihydrate The crude 2,8-distyryl-4,6-dioxo-l0-methyl-4H, 6H-benzo (1,2-b: 5,4-b') dipyran obtained byhydroxy-4H, 101-1 benzo (1,2-b: 3,4-b') dipyran trihydrate (0.1 parts)melting point 312 C.(d).

Analysis Found C I-LO BrM-LO requires:

C, 37.0 H, 1.82% C, 37.25 H, 2.44%

6-Bromo-2,8-dicarboxy-4,10-dioxo-5-hydroxy- 4H, IOH-benzo (1,2-b:3,4-b') dipyran disodium salt A solution of 6-bromo-2,8-dicarboxy-4,IO-dioxo- 5-hydroxy-4H, IOH-benzo (1,2-b: 3,4-b') water and extractedinto aqueous sodium bicarbonate solution. Upon acidification of thesolution, a precipitate was formed which was filtered off and dried toyield 2,8-dicarboxy-4, 6-dioxo- 10-methyl-4H, 6H-benzo (1,2-b: 5,4-b')dipyran hemihydrate, which was shown to be identical with the product ofExamples 10 and l 1.

dipyran trihydrate (0.08 parts) and sodium bicarbonate (0.035 parts) inwater (10 parts) was freeze dried to give 6-bromo-2,8-dicarboxy- 4,10-dioxo-5-hydroxy-4H, IOH-benzo (1,2-b: 3,4-b) dipyran disodium salt(0.08 parts).

EXAMPLE 14 The processes described in Examples 1 to 13 were repeatedusing different reactants and Table I sets out the products obtained,the Example number of the process route employed and the physicalcharacteristics of the products, where measured.

EXAMPLE l3 6-Bromo-2 ,8 -dicarboxy-4,l O-dioxo-S -hydr oxy-4H IOH-benzo1,2-b: 3 ,4-b) dipyran.

a. 2,8-Diethoxycarbonyl-4,lO-dioxo-5-hydroxy-4H,

IOH-benzo (1,2-b: 3,4-b) dipyran A solution of2,8-dicarboxy-4,l0-dioxo-5-hydroxy TABLE 1 Example Physical data, wheremeasured sodium bicarbonate. Acidification of the bicarbonate solutionwith dilute hydrochloric acid gave 6-bromo-2,8-dicarboxy-4, IO-dioxo-S-4,10-Dioxo-5-methyl- 2,8-dicarboxy- 4H,10H'benzo (1,2- b:3,4-b') dipyran4H 1()H b (1 2..b; 3 44,) di Name of Compound Number Melting AnalysisFound monohydrate (1.76 parts prepared as in Exam- 3 ple 2) andconcentrated sulphuric acid (0.5 g in C H Ot r% parts) in ethanol (150parts) was refluxed for 4 om hours. The solid obtained on cooling wasfiltered off to give 1.85 parts of 2,8-diethoxycarbonyl-4,l0-dioxo-5-hydroxy-4H, IOH-benzo (1,2-b: 3,4- I b) dipyran (1.35 parts)as a brown solid. 'f f%:: "f"i g;3,4-b')2%ipyran 1 225-6 60.34 3.85 4ioxo- Analysis:

Found: c 57.0% a 3.81% 40 gq' g fgffl. C H O Iequires cs7.7% H 3.77% dig a f Melting point 171C. a l 466 L67 4,l( )-dioxo-2,B- 6-Bromo-2,8-diethoxycarbonyl-4, l O-dioxo-S g" 8[f;m' hydroxytl-l, IOI-l-benzo(1,2-b: 3,4-b') dipyran b;3',4 -b') dipyran 1 183-4 60.79 3.74 To asolution of 2,8-Diethoxycarbonyl-4,10-dioxo- 1 223 8332; 0H

5-hydroxy'4l-l, IOH-benzo (1,2-b: 3,4-b') hem Y2 b;5 4 dipyran (0.5parts as prepared above) in glacial di disodium 44 6 2 09 acetic acid(10 parts) was added a solution of 5 4 10 bromine (0.1 parts) in glacialaceticacid. The sl gbo l le OX car n solution was heated at 100 C. for 6hours and mrlofllfbenzo then the acetic acid was evaporated. The oilyb;3,4- product was triturated with cold ethanol and the g' x 10 l 210412resulting solid was filtered off to give 6-bromodioxo-2,B-dicarboxy- 2,8-diethoxycarbonyl-4, 1 0-dioxo-5 -hydroxy- 5 5 gg mm g g zg 4H,IOH-benzo (1,2-b: 3,4- dipyran 0.4 sesquihydrate 1 272-5 5.7.6 3.42

S-Ben lox -4,10- part s) as a pale brown solid, melting point dio 31dicarboxy 1 9 -2 2 C- 4H,10H-benzo(l,2- 6-Bromo-2,8-dicarboxy-4,10-dioxo-5-hydroxyflgg ttg'g i py 1 4n, IOH-benzo 1,24); 3,4-b') dipyrantrihydrate f A solution of 6-brom0-2,8-diethoxycarbonyl-4, yi10-dioxo-5-hydroxy-4H, IOH-benzo (1,2-b: 3,4- ;P 1 287 5m m b) dipyran(0.4 parts as prepared above) in Sesquihydrate (via (decomp) aqueousethanol (25 parts) was hydrolyzed with 65 2:22

disodium salt 5-Methoxy-4,6-dioxo- 2,8- diethoxycarbonyl- 4H,6H-benzo(1,2- b:-5,4b) dipyran 5-Methoxy-4,6-dioxo- 2,8-dicarboxy- 4l-l,6H-benzo(1,21):- 5.41:) dipyran disodium salt 4,10-Dioxo-6-ethyl- 2,8-dicarboxy-411,10l-l-benzo (1,2- b: 3,4-b') dipyran monohydrate 4,10-Dioxo-6-ethyl-2,8-dicarboxy- 411,101-l-benzo (1,2- b: 3,4-b') dipyran disodium salt4,6;Dioxo-2,8-

dicarboxy-lO- methyl-411,6H-benzo (1,2-b: 5,4-b') dipyran hemihydrate4,6-dioxo-2,8-

dicarboxyl methyl-4l-l, 6H- benzo (1,2-b: 5,4-b') dipyran disodium salthemihydrate 4,6-Dioxo-2,8-

dicarboxy- 1 O-ethyl- 4H, 6l-l-benzo (1,2- b:5,4-b') dipyran disodiumsalt 4,6 -Dioxo-2,8-

diethoxycarbonyll0-ethyl-4l-l, 6H- benzo (1,2-b: 5,4-b') dipyran4,6-Dioxo-2,8-

diethoxycarbonyll0-nitro-4l-1,6H- benzo (1,2-b:5,4-b') dipyran4,6-Dioxo-2,8-

dicarboxy-lO-nitro- 4H, 6l-l-benzo (1,2- b: 5,4-b') dipyran hemihydrate4,6-Dioxo-2,8-

dicarboxyl O-nitro- 41-1, 6H-benzo (1,2- b: 5.4-b') dipyran disodiumsalt 6,10-dicarboxy-4- methyl-2,8,12- trioxo-2H,8l-l,l21lbenzo (1,2-b:3,4-b':

5,6-b") tripyran trihydrate 6,10-dicarboxy-4- methyl-2,8,12-trioxo-2H,8H,l2l-lbenzo (1,2-b: 3,4-b':

5,6-b") tripyran disodium salt 3,4-b') di yran di yran dihydrate 6-romo-2,8-

dicarboxy-4, l O- dioxo--hydroxy-4l-l, lOH-benzo (1,2- b:3,4-b') dipyrandisodium salt 1 (via ethyl ester) l (via ethyl ester)4,10-dioxo-6-chloro- 2.8-dicarboxy- 4H,l0H-benzo (1,2- b:3,4-b )dipyranmonohydrate 2 4,10-dioxo-6-chloro- 2,8-dicarboxy- 4H,l0H-benzo (1,2-b:3,4-b') dipyran disodium salt 4,l0-dioxo2,8-

dicarboxy-S-allyloxy- 4H,l0H-benzo (1,2- b:3,4-b') dipyran hemihydrate 14,l0-dioxo-2,3-

dicarboxy-S-allyloxy- 4H, loll-benzo (1,2- b:3,4-b') dipyran disodiumsalt Example 15 10-Butyl-2,8-dicarboxy-4,6-dioxo-4l-1,6H-benzo 1,2- b:5,4-b'] dipyran Analysis C, 67.0 H, 7.25% C, 67.18 H, 7.25%

Found: 14 150 requires:

b. l0-Butyl-2,8-diethoxycarbonyl-4,6-dioxo-4l-1,61-1- benzo [1,2-b:5,4-b] dipyran To a stirred solution of 2.1 parts of sodium in 60 partsof dry ethanol was added a slurry of 2.5 parts of4,6-diacetyl-2-n-butylresorcinol and 7.3 parts of diethyl oxalate in 50parts of dry ethanol. The mixture was stirred and heated under refluxfor 4 hours.

After cooling, the mixture was poured into a separating funnelcontaining ethyl acetate and dilute hydrochloric acid. The ethyl acetatelayer was separated, dried over sodium sulphate and evaporated to leavean oil.

This oil was dissolved in parts of ethanol containing 2.0 parts ofconcentrated hydrochloric acid and the solution was heated under refluxfor 30 minutes. The volume was reduced to 50 ml. then thesolution wasallowed to cool whence a solid crystallized. This solid wasrecrystallized from ethanol to give IO-butyl-2,8-diethoxycarbonyl-4,6-dioxo-4l-1,6l-l-benzo [1,2-b: 5,4-b'] dipyranas colorless needles, melting point l55157C.

Analysis Found: .7 H C l-1 0 requires: C, 63.76 H,

c. lO-Butyl-Z,8-dicarboxy-4,6-dioxo-4l-l,6H-benzo 1 ,2-b: 5 ,4-b']dipyran hemihydrate portion was extracted repeatedly with 2N sodie.2,8-Dicarboxy-5-methoxy-4,6-dioxo-IO-propylum hydroxide solution, whichwas then acidified 4H,6H-benzo [1,2-b: 5,4-b] dipyran to give2,6-diacetyl-3-allyloxy-5-benzyloxy- By the method of Example 15 (c) 2.4parts of 2,8-

phenol as pale yellow needles, melting pointdiethoxy-carbonyl-S-methoxy-4,6-dioxo-l- 92-92.5C.propyl-4l-l,6l-l-benzo [1,2-b: 5,4-b] dipyran were converted into2,8-dicarboxy-5-methoxy- Analysis 4,6-dioxo--propyl-4l-l,6H-benzo[1,2-b: 5,4-

Found: C, 70.6 H,5.84% r O O cmHmosrequim: Q70 532% b ]dipyran,meltmgpoint 278 279 C.(d).

l0 b.2,6-Diacetyl-3-allyloxy-5-benzyloxyanisole Analym Found: C 578 H3.74% A mixture of 6 parts of 2,6-diacetyl-3-allyloxy-5- C H O,requires: C 57.8 H, 3.77%

benzyloxyphenol, 6.5 parts of anhydrous potassium carbonate, 7.5 partsof dimethyl sulphate, f. and 100 parts of dry acetone was refluxed withstirring for 16 hours. The mixture was diluted2,8-Dicarboxy-5-methoxy-4,6-dioxol O-propyl- 4H,6H-benzo [1,2-b: 5,4-b']dipyran disodium salt By the method of Example 15 (d) 0.567 parts ofwith water, acidified, and extracted with ether, which was washed withwater, dried and .evaporated to yield an oil. The oil solidified ontracted with hot light petroleum (b.p. 4060). The extracts wereevaporated and distilled at l50l70 C/0.6 mm to give a viscous oil, whichwas crystallized from aqueous ethanol to afford converted into2,8-diethoxycarbonyl-5-methoxy-4,6-dioxo-10-propyl-4H,6H-benzo 1,2-b: 5,4- b'] dipyran, melting point l68-168.5 C.

Found: C l- 0 requires:

2 ,8-dicarboxy-5-methoxy-4,6-dioxol O-propyl- 4l-I,6H-benzo [1,2-b:5,4-b'] dipyran were converted into2,8-dicarboxy-5-methoxy-4,6-dioxostanding and was recrystallized fromaqueous 20 l0-propyl-4H,6H-benzo [1,2-b: 5,4-b'] dipyran ethanol aftertreatment with charcoal to give, disodium salt. 2,6-diacet l-3-a11 lox-5-benz lox -anisole as prisms, m lting pgint l7-78 y Example 192,8-Dicarboxy-5-methoxy-4, l 0-dioxo-6-propyl-4H, Found: c,71.2 H, 6.29%loH'benzo C l- 0 requires: C, 71.2 H, 6.26% 1,24): py

c. 4,6-Diacetyl-5-methoxy-2-propylresorcinol a.2,4-Diacetyl-6-allyl-5-methoxyresorcinol Under an atmosphere of nitrogen6.6 parts of 2,6- A mixture of 15.5 parts of2,4-diacetyl-5-allyloxdiacetyl-3-allyloxy-5-benzyloxyanisole' and 15yresorcinol, 8.6 parts of anhydrous potassium parts of tetralinwererefluxed for 4 hours. The carbonate, 10 parts of methyl iodide, and 80mixture was cooled, diluted with light petroleum parts of acetone wasrefluxed for 16 hours. Most (b.p. 40-60) and extracted repeatedly with2N of the acetone was removed and the residue was sodium hydroxide. Thecombined alkaline exdiluted with water, acidified, and extracted withtracts were washed with light petroleum, ether, which yielded 17 partsof an oil on acidified, and extracted with ether, which was evaporation.The oil was refluxed with 17 parts then evaporated to give 2.4parts of ared oil. of tetralin for 3.5 hours. The mixture was cooled The oil wastaken up in 100 parts of ethanol conand poured into 2N sodium hydroxidesolution. taining 2 drops of concentrated hydrochloric The aqueous layerwas washed with benzene, acid, and hydrogenated at p.s.i. for one hourand then extracted repeatedly with ethyl over 0.5 parts of 5% palladiumon charcoal. The acetate. The combined ethyl acetate portions mixturewas filtered and evaporated to yield 1.7 were evaporated to give asolid, which crystalparts of a red oil, which was repeatedly ex- 45lized from aqueous ethanol to afford f2,4-

diacetyl-6-allyl-5-methoxy-resorcinol as long fibrous needles, meltingpoint 84.585 C.

4,6-diacetyl-5 -methoxy-Z-propylresorcinol as 5 CHHWO z f ii 23:2 22:32needles, melting point 80 C.

b. 2,4-Diacetyl-5-methoxy-6-propylresorcinol Found, C, 633 H. 65% Anethanolic solution of 1.3 parts of 2,4-diacetyl- C I-1, 0, requires: C,63.1 H, 6.81% 6-allyl-5-methoxyresorcinol was hydrogenated at 45 p.s.i.for 2 hours over 0.5 parts of 5% pal-2,8-Diethoxycarbonyl-5-methoxy-4,6dioxo-10- ladium on charcoal. Themixture was filtered propyl-4l-l,6H-benzo [1,2-b: 5,4-b'] dipyran. andevaporated to give a green oil which crystaL By the method of Example 15(b) 4.0 parts of 4,6- lized from aqueous ethanol to afford 2,4-

diacetyl-S-methoxy-2-propylresorcinol werediacetyl-S-methoxy-6-propylresorcinol as long needles, melting point4849 C.

Found: C, 62.7 H, 6.85% c r-n.0, requires: C, 63.1 H, 6.76%

2,8-Diethylcarbonyl-5 -methoxy-4, l O-dioxo-6- propyl-4H,l OH-benzo l,2-b: 3,4-b'] dipyran A solution 2.0 parts of10-butyl-2,8-diethoxycarbonyl-4,6-dioxo-4H,6-benzo [1,2-b: 5,4-b']dipyran and 1.22 parts of sodium bicarbonate in aqueous ethanol washeated till thin layer chromatography showed that the ester had beencompletely hydrolyzed. The solution was then cooled and acidified withdilute hydrochloric acid to give a white precipitate. This solid wasfiltered off and boiled with ethanol. This procedure left 0.8 parts ofl-butyl-2,8-dicarboxy-4,6-dioxo-4l-l,6H-benzo [1,2-b: 5,4-b'] dipyranhemihydrate as the insoluble product, melting point 314C. (d).

Analysis Found: C l-l O bH O requires:

d. -Butyl-2,8-dicarboxy-4,6-dioxo-4H,6l-l-benzo 1,2-b: 5,4-b'] dipyrandisodium salt A solution of 0.6 parts of l0-butyl-2,8-dicarboxy-4,6-dioxo-4l-l,6H-benzo [1,2-b: 5,4-b'] dipyran hemihydrate and 0.27parts of sodium bicarbonate in 50 parts of water was freeze-dried togive 10-butyl-2,8-dicarboxy-4,6-dioxo-4H,6H- benzo [1,2-b: 5,4-b']dipyran disodium salt.

Example 16 2,6,l0-Tricarboxy-4,8,12-trioxo-4,8,l2-trioxo-4H,8H,l2H-benzo [1,2-b: 3,4-b:5,6-b] tripyran 2,6,l0-Tricarboxy-4,8,l2-trioxo-4l-l,8l-l,12l-lbenzo [1,2-b: 3,4-b: 5,6-b"]tripyran hemihydrate To a stirred solution of 2.76 parts of sodium in 50parts of dry ethanol was added a slurry of 2.52

parts of triacetylphloroglucinol and l 1.0 parts of diethyl oxalate in50 parts of dry ethanol. The mixture was stirred and heated under refluxfor 4 hours.

After cooling, the mixture was poured into a separating funnelcontaining a mixture of ethyl acetate and dilute hydrochloric acid. Theethyl acetate layer was separated, dried over sodium sulphate andevaporated to leave an oil. This oil was dissolved in 50 parts ofethanol containing 0.5 parts of concentrated hydrochloric acid and thesolution was refluxed for 30 minutes. The volume was then reduced to 30ml. and allowed to cool whence a brown solid crystallized out. Thissolid was redissolved in aqueous ethanol and treated with sodiumbicarbonate. The solution was then heated till thin layer chromatographyshowed that hydrolysis was complete. The solution was cooled andacidified to give 2,6,l0-tricarboxy-4,8,l2-trioxo-4 H,8H,12-benzo[1,2-b: 3,4-b: 5,6-b"] tripyran hemihydrate as a yellow solid, meltingpoint 275-277 C.

Analysis Found: C H.O %H,O requires:

b. 2,6,l0-Tricarboxy-4,8,l2-trioxo-4H,8H,12H-

benzo [1,2-b: 3,4-b': 5,6-b"] tripyran trisodium salt By the method ofExample (d) 0.088 parts of 2,6,l0-tricarboxy-4,8,l2-trioxo-4H,8H,l2H-benzo [1,2-b: 3,4-b: 5,6-b"] tripyran hemihydrate was converted into2,6,10-tricarboxy-4,8,l2-trioxo-4H,8H,l 2H-benzo [1,2-b: 3,4-b': 5,6-b"]tripyran trisodium salt.

Example 17 2,8-Dicarboxy-4,6-dioxo-l0-n-pentyl-4H,6H-benzo ]1,2-b:5',4-b] dipyran Analysis C,68.l H, 7.71% C. 68.16 H, 7.63%

Found: C H O requires:

b. 4,6-Diacetyl-2-n-pentylresorcinol By the method of Example 15 (a) 4,4parts of 2,6-

diacetyl-n-pentylbenzene were converted into4,6-diacetyl-2-n-pentylresorcinol. This compound was not completelypurified but was used directly for the next stage of the reaction. c.2,8-Dicarboxy-4,6-dioxo-l0-n-pentyl-4l-l,6l-lbenzo [1,2-b: 5,4-b]dipyran By the method of Example 16 (a) 1.34 parts of crude4,6-diacetyl-2-n-pentylresorcinol were converted into2,8-dicarboxy-4,6-dioxo-l0-npentyl-4H,6H-benzo [1,2-b: 5,4-b'] dipyran,melting point 268 C. (d).

Analysis Found: C, 61.1 H, 4.76% c u o. requires: C, 61.29 H, 4.33%

d. 2,8-Dicarboxy-4,6-dioxo-l0-n-pentyl-4H,6H-

benzo [1,2-b: 5,4-b'] dipyran disodium salt By the method of Example 15(d) 0.046 parts of 2,8-dicarboxy-4,6-dioxol 0-n-pentyl-4H ,6H- benzo[1,2-b: 5,4-b'] dipyran were converted into 2,8-dicarboxy-4,6-dioxolO-n-pentyl- 4l-l,6H-benzo [1,2-b: 5,4-b'] dipyran disodium salt.

Example 182,8-Dicarboxy-5-methoxy-4,6-dioxo-10-propyl-4H,6l-lbenzo-[1,2-b: 5,4-b]dipyran a. 2,6-Diacetyl-3-allyloxy-5-benzyloxyphenol A mixture of 13.5parts of 2,4-diacetyl-5-al1yloxyresorcinol, 7.5 parts of anhydrouspotassium carbonate, 13 parts of benzyl chloride, 0.5 parts of potassiumiodide, and 60 parts of dry acetone was stirred and refluxed for 43hours. Most of the acetone was removed, and the residue was mixed withwater and acidified to give an orange oil, which was extracted withether. The ethereal By the method of Example 15 (b) 4.0 parts of 2,4-

diacetyl-S -methoxy-fi-propylresorcinol were converted to2,8-diethoxycarbonyl-5-methoxy- 4,10-dioxo-6-propyl-4H,1OI-l-benzo[1,2-b: 3 ,4- b'] dipyran, melting point 154-155 C.

with aqueous ethanol, filtered off and dried, then dissolved in sodiumbicarbonate solution and reprecipitated with hydrochloric acid, thenagain filtered off and dried to leave2,8-dicarboxy-l-ethyl-5-methyl-4,6-dioxo-4H,6H-benzo [1,2b: 5,4-b']dipyran hemihydrate, melting point 312 C. (d).

Analysis Found: C, 61.2 H, 5.08% C ll O, requires: C, 61.4 H, 5.15%

d. 2,8-Dicarboxy--methoxy-4,l0-dioxo-6-propyl- 10 41-l,10H-benzo [1,2-b:3,4-b'] dipyran hemihydrate 7 By the method of Example (c) 0.5 parts of2,8-

diethoxycarbonyl-S-methoxy-4,10-dioxo-6- propyl-4l-l,l0H-benzo [1,2-b:3,4-b'] dipyran 15 were converted into 2,8-dicarboxy-5-methoxy-4,10-dioxo-6-propyl-4l-l,lOH-benzo [1,2-b: 3,4-

b'] dipyran hemihydrate, melting point'268-27 c.2,8Dicarboxy-l0-ethyl-5-methyl-4,6-dioxo-4l-l,6

0 C. H-benzo [1,2-b: 5,4-b'] dipyran disodium salt By the method ofExample 15 (d) 0.38 parts of 2,8-dicarboxyl O-ethyl-S -m ethyl-4,6-dioxo- 4H,6H-benzo 1,2-b: 5,4-b'] dipyran hemihydrate were convertedinto 2,8-dicarboxyb: 5,4-b'] dipyran disodium salt.

Found: C, 57.6 H, 3.54% c.,n.,o,-%H,o requires: C. 57.7 H, 3.68%

Analysis Found: C, 55.8 1-1 3.47% C l-l, 0,%l-1,Q requires: C, 56.4 H,3.9%

e. 2,8-Dicarboxy-5-methoxy-4,l0-dioxo-6-propyl- 4H,l01-l-benzo [1,2-b:3,4-b'] dipyran disodium salt By the method of Example 15 (d) 0.132parts of 2,8-dicarboxy-5-methoxy-4,l0-dioxo-6-propyl- 4I-l,10l-l-benzo[1,2-b: 3,4-b'] dipyran hemihydrate were converted into 2,8-dicarboxy-5-methoxy-4,l0-dioxo-6-propyl-4H,IOH-benzo [1,2-b: 3,4-b] dipyrandisodium salt.

Example 21 2,7-Dicarboxy-4,9-dioxo-4H,9H-benzo [1,2-b: 4,5-b'] dipyrana. 2,7-Diethoxycarbonyl-4,9-dioxo-4l-I,9H-benzo [1,2-b: 4,5-b'] dipyranBy the method of Example 15 (b) 2.4 parts of 1,4-

diacetyl-2,S-dihydroxybenzene were converted into2,7-diethoxy-carbonyl-4,9-dioxo-4H,9H- benzo [1,2-b: 4,5-b'] dipyran,melting point 244-245 C.

Example 20 3 5 2,8-Dicarboxy-10-ethyl-5-methyl-4,6-dioxo-4H,61-1- benzo[1,2-b: 5,4-b'] dipyran a. 1,3-Bis-( 1,2-trans-dicarboxyvinyloxy)-2-ethyl-5- methylbenzene 40 A solution of 3parts of 2-ethyl-5-methylresorcinol and 6.5 parts of dimethylacetylnedicarboxylate in 10 parts of dioxan was treated with 3 drops ofa 40% aqueous solution of benzyltrimethyl-ammonium hydroxide andsubsequently heated on Analysis Found:

C, 60.2 H, 3. C I-1, 0 requires: H 3

a steam-bath for 15 minutes. The mixture was then cooled and treatedwith 30 parts of a 25% sodium hydroxide solution in water andrediethoxycarbonyl-4,9-dioxo-4l-l,9H-benzo l ,2- b: 4,5-b'] dipyran wereconverted into 2,7- dicarboxy-4,9-dioxo-4H,9l-l-benzo [1,2-b: 4,5-

heated on a steam-bath for 20 minutes. The mixb'] dipyran hemihydrate,melting point 340 ture was cooled, washed with ether to remove C.dioxan, acidified with sulphuric acid and extracted with ether.Evaporation of the second Analysis d C H 6% Foun 53.4 2.3 etherealsolution left l,3-bis-(1,2-trans-d1carcuflwofimowquires: C, 530 2.25%

boxyvinyloxy)-2-ethyl-5-methylbenzene, melt- 55 ing l 162's c.2,7-Dicarboxy-4,9-dioxo-4l-l,QH-benzo 4,5-b'] dipyran disodium saltAnalysis Found: G510 H, 433% By the method of Example 15 (d) 0.154 partsof c n o requires: c, 53.65 H, 4.21%2,7-dicarboxy-4,9-dioxo-4l-1,9l-l-benzo [1,2-b:

4,5-b] dipyran hemihydrate were converted b.2,8-Dicarboxy-10-ethyl-5-methyl-4,6-dioxo-4ll,6 into2,7-dicarboxy-4,9-dioxo-4l-l,9H-benzo H-benzo [1,2-b: 5,4-b'] dipyranhemihydrate To a stirred solution of 25 parts of chlorosulphonic acidwas added, in small lots, 3 parts of 1,3-bisl,2-trans-dicarboxyvinyloxy)-2-ethyl5- methylbenzene. The solution wasallowed to stand for 10 minutes then it was carefully diluted [1,2-b:4,5-b'] dipyran disodium salt.

EXAMPLE 22 The compounds described in Table II were tested to assesstheir acute toxicity and their effectiveness in inhibitingantibody-antigen reactions.

2. A compound according to claim 1, wherein those of P, Q, R and T notforming a-CO-CR1 C(COOH)-O- chain are hydrogen or halogen, hydroxy,nitro, lower alkyl, lower alkenyl, benzyl, phenyl, lower alkoxy, loweralkenyloxy, phenyl, benzyloxy or the fused ring substituents specifiedin claim 1 or such groups carrying a halogen, hydroxy or lower alkoxysubstituent.
 3. A compound according to claim 1, wherein those of P, Q,R and T not forming a -CO-CR1 C(COOH)-O- chain are hydrogen, chlorine,bromine, nitro or lower alkyl or alkoxy grOup containing from one to sixcarbon atoms which may carry a hydroxy, lower alkoxy or phenylsubstituent.
 4. A compound according to chain 1 and of formula, whereinan adjacent pair of P1, Q1, R1 and T1 together forms the chain -CO-CHC(COOH)-O- which may be bonded to the benzene ring in either sense; andthe other two P1, Q1, R1 and T1 may be the same or different and each ishydrogen, halogen, nitro, lower alkyl, lower alkoxy, or a lower alkyl oralkoxy group carrying a hydroxy, lower alkoxy or phenyl substituent. 5.A compound according to claim 1 in which those of P, Q, R and T which donot form a chain -COCR1 C(COOH)-O- are selected from the groupconsisting of hydrogen, hydroxy, nitro, halogen, lower alkyl, loweralkoxy or lower alkenyloxy groups (which groups may carry a hydroxy orlower alkoxy substituent), a benzyl group or an adjacent pair of P, Q, Rand T may, form a chain -O-(CH2)2, and each R1 is selected from thegroup consisting of hydrogen, alkyl containing from one to 10 carbonatoms, alkoxy containing from 1 to 10 carbon atoms and phenyl.
 6. Acompound according to claim 1 in which R1 is hydrogen and those of P,Q,Rand T which do not form a -COCR1 (COOH)-O-chain are selected frommethoxy, hydroxy, nitro, methyl, bromo, benzyloxy, ethyl, chloro,allyloxy, butyl, propyl and pentyl.
 7. A compound according to claim 1,vis., 4, 10-Dioxo-5-methoxy-2,8-dicarboxy-4H,10H-benzo (1,2-b:-3,4-b'')dipyran and the sodium salt thereof.
 8. A compound according to claim 1,vis., 4,10-Dioxo-2,8-dicarboxy-5-hydroxy-4H 10H-benzo (1,2-b: 3,4-b'')dipyran and the sodium salt thereof.
 9. A compound according to claim 1,vis., 4,10-Dioxo-5-methyl-2, 8-dicarboxy-4H,10H-benzo (1,2-b:3,4-b'')dipyran and the sodium salt thereof.
 10. A compound according to claim1, vis., 2,8-Diethoxycarbonyl-4, 10-dioxo-4H, 10H-benzo (1,2b: 3,4-b'')dipyran and the sodium salt thereof.
 11. A compound according to claim1, vis., 2,8-Dicarboxy-4,6-dioxo-10-nitro-4H,6H-benzo (1,2-b:5,4-b'')dipyran and the sodium salt thereof.
 12. A compound according to claim1, vis., 2,8-Dicarboxy-4,6-dioxo-10 methyl -4H, 6H-benzo (1,2-b:5,4-b'') dipyran and the sodium salt thereof.
 13. A compound accordingto claim 1, vis.,6-Bromo-2,8-dicarboxy-4,10-dioxo-5-hydroxy-4H,10H-benzo (1,2-b:3,4-b'')dipyran and the sodium salt thereof.
 14. A compound according to claim1, vis., 4,6-dioxo-2,8-dicarboxy-4H,6H-benzo (1,2-b:5,4-b'') dipyran andthe sodium salt thereof.
 15. A compound according to claim 1, vis.,5-Benzyloxy-4,10-dioxo-2,8-dicarboxy-4H,10H-benzo (1,2-b:3,4-b'')dipyran and the sodium salt thereof.
 16. A compound according to claim1, vis., 5-Methoxy-4,6-dioxo-2,8-dicarboxy-4H,6H-benzo (1,2b:-5,4b'')dipyran and the sodium salt thereof.
 17. A compound according to claim1, vis., 4,10-Dioxo-6-ethyl-2, 8-dicarboxy-4H,10H-benzo (1,2-b: 3,4-b'')dipyran and the sodium salt thereof.
 18. A compound according to claim1, vis., 4,6-Dioxo-2,8-dicarboxy-10-ethyl-4H, 6H-benzo (1,2-b:5,4-b'')dipyran and the sodium salt thereof.
 19. A compound according to claim1, vis., 6,10-dicarboxy-4-methyl-2,8,12-trioxo-2H,8H,12H-benzo (1,2-b:3,4-b'': 5,6-b'''')tripyran and the sodium salt thereof.
 20. A compoundaccording to claim 1, vis.,4,10-dioxo-2,8-dicarboxy-5-allyloxy-4H,10H-benzo (1,2-b:3,4-b'') dipyran21. A compound according to claim 1, vis.,10-Butyl-2,8-dicarboxy-4,6-dioxo-4H,6H-benzo (1,2-b: 5,4-b'') dipyran22. A compound according to claim 1, vis.,2,6,10,10-Tricarboxy-4,8,12-trioxo-4H,8H12H-benzo (1,2-b: 3,4-b'':5,6-b'''') tripyran and the sodium salt thereof.
 23. A compoundaccording to claim 1, vis.,2,8-Dicarboxy-4,6-dioxo-10-n-pentyl-4H,6H-benzo (1,2-b: 5,4-b'') dipyran24. A compound according to claim 1, vis.,2,8-Dicarboxy-5-methoxy-4,6-dioxo-10-propyl-4H,6H-benzo (1,2-b: 5,4-b'')dipyran
 25. A compound according to claim 1, vis.,2,8-Dicarboxy-5-methoxy-4,10-dioxo-6-propyl-4H,10H-benzo (1,2-b:3,4-b'') dipyran
 26. A compound according to claim 1, vis.,2,8-Dicarboxy-10-ethyl-5-methyl-4,6-dioxo-4H,6H-benzo (1,2-b: 5,4-b'')dipyran
 27. A compound according to claim 1, vis.,2,7-Dicarboxy-4,9-dioxo-4H,9H-benzo (1,2-b: 4,5-b'') dipyran and thesodium salt thereof.
 28. A compound according to claim 1, vis.,4,10-dioxo-6-chloro-2,8-dicarboxy-4H,10H-benzo (1,2-b:3,4-b'') dipyran